title: Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA.
abstract: Primary pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by accumulation of surfactant in the lungs that is presumed to be mediated by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling based on studies in genetically modified mice. The effects of GM-CSF are mediated by heterologous receptors composed of GM-CSF binding (GM-CSF-Ralpha) and nonbinding affinity-enhancing (GM-CSF-Rbeta) subunits. We describe PAP, failure to thrive, and increased GM-CSF levels in two sisters aged 6 and 8 yr with abnormalities of both GM-CSF-Ralpha-encoding alleles (CSF2RA). One was a 1.6-Mb deletion in the pseudoautosomal region of one maternal X chromosome encompassing CSF2RA. The other, a point mutation in the paternal X chromosome allele encoding a G174R substitution, altered an N-linked glycosylation site within the cytokine binding domain and glycosylation of GM-CSF-Ralpha, severely reducing GM-CSF binding, receptor signaling, and GM-CSF-dependent functions in primary myeloid cells. Transfection of cloned cDNAs faithfully reproduced the signaling defect at physiological GM-CSF concentrations. Interestingly, at high GM-CSF concentrations similar to those observed in the index patient, signaling was partially rescued, thereby providing a molecular explanation for the slow progression of disease in these children. These results establish that GM-CSF signaling is critical for surfactant homeostasis in humans and demonstrate that mutations in CSF2RA cause familial PAP.
authors.affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Takuji
authors.initials: T
authors.lastname: Suzuki
authors.forename: Takuro
authors.initials: T
authors.lastname: Sakagami
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Rubin
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Nogee
authors.forename: Robert E
authors.initials: RE
authors.lastname: Wood
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Zimmerman
authors.forename: Teresa
authors.initials: T
authors.lastname: Smolarek
authors.forename: Megan K
authors.initials: MK
authors.lastname: Dishop
authors.forename: Susan E
authors.initials: SE
authors.lastname: Wert
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
authors.forename: Gregory
authors.initials: G
authors.lastname: Grabowski
authors.forename: Brenna C
authors.initials: BC
authors.lastname: Carey
authors.forename: Carrie
authors.initials: C
authors.lastname: Stevens
authors.forename: Johannes C M
authors.initials: JC
authors.lastname: van der Loo
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Trapnell
mesh_terms: D000818:Animals; D002648:Child; D041321:Chromosomes, Human, X; D004252:DNA Mutational Analysis; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D011649:Pulmonary Alveolar Proteinosis / Q000235:genetics* / Q000503:physiopathology; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: C521678:CSF2RA protein, human; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor